This application requests funding to undertake innovative research on a large-scale population-based Seek, Test, Treat and Retain (STTR) initiative. The Province of British Columbia (Canada) has embarked upon one of the world's largest and most advanced STTR initiatives, which was renewed in November 2012. The universal healthcare system within the province provides all medical care, including highly active antiretroviral therapy (HAART) and substance abuse treatment, free of charge. Extensive confidential record linkages allow the accurate attainment of all key measures, including health service utilization and HIV clinical outcomes. Taking advantage of this initiative and a large linked database, as well as the interdisciplinary research capacity of the British Columbia Centre for Excellence in HIV/AIDS (Vancouver), herein we propose a program of rigorous and innovative study that will marshal epidemiologic, clinical, geographic, and phylogenetic approaches to critically inform efforts to respond to HIV transmission and pathogenesis among HIV-infected individuals, with a particular emphasis on individuals who inject drugs (IDU). Specifically, we seek to augment our ongoing epidemiologic and clinical research activities with molecular genetics and geographic information systems (GIS) based methods to model the effect of this STTR initiative on the generation of antiretroviral drug resistance and HIV incidence. As well, we will use novel phylogenetic methods and next generation sequencing to assess the suitability of new HIV diagnoses as a surrogate for HIV incidence. In order to aid in the optimization of STTR approaches, we will also identify patterns and predictors of engagement in and leakage from the Cascade of Care' among IDU. Lastly, by integrating GIS with phylogenetic data, we will identify unrecognized foci of HIV transmission throughout the province. This proposal comes at a time of international consensus on the need to respond urgently to elevated levels of HIV-related morbidity and mortality, particularly among IDU. Evidence from mathematical modeling, observational cohorts and clinical trials has revealed the close link between HAART access and the risk of HIV transmission between individuals, resulting in markedly lower rates of infection in populations with higher levels of coverage of HAART. This observation has led to renewed HIV prevention efforts to seek out members of vulnerable populations, test them for HIV infection, and engage them in healthcare, including treatment for HIV infection, in order to reduce HIV-related morbidity and mortality and lower HIV incidence. Given the research infrastructure established to date and our track record in undertaking novel and high impact research on STTR, we are uniquely well placed to prospectively assess key second-generation questions regarding the impact of STTR on engagement in treatment and care, HAART resistance, and HIV incidence. The work proposed herein is strongly aligned with the priorities in the FY 2013 Trans-NIH Plan for HIV-Related Research.